Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial

Arabi, Yaseen M.; Asiri, Ayed Y.; Assiri, Abdullah M.; Aziz Jokhdar, Hani A.; Alothman, Adel; Balkhy, Hanan H.; AlJohani, Sameera; Al Harbi, Shmeylan; Kojan, Suleiman; Al Jeraisy, Majed; Deeb, Ahmad M.; Memish, Ziad A.; Ghazal, Sameeh; Al Faraj, Sarah; Al-Hameed, Fahad; AlSaedi, Asim; Mandourah, Yasser; Al Mekhlafi, Ghaleb A.; Sherbeeni, Nisreen Murad; Elzein, Fatehi Elnour; Almotairi, Abdullah; Al Bshabshe, Ali; Kharaba, Ayman; Jose, Jesna; Al Harthy, Abdulrahman; Al Sulaiman, Mohammed; Mady, Ahmed; Fowler, Robert A.; Hayden, Frederick G.; Al-Dawood, Abdulaziz; Abdelzaher, Mohamed; Bajhmom, Wail; Hussein, Mohamed A.

There are several challenges in a trial for treatment of a disease like MERS: (1) there is not enough information on the effect size of the lopinavir/ritonavir and interferon-β1b provided with standard supportive care compared to placebo provided with standard supportive care to conduct adequate planning for the study sample size; (2) MERS is a sporadic, unpredictable, and rare disease, which makes it difficult to plan a separate pilot study to collect the necessary information needed for the planning of the main trial. To overcome these challenges, we designed the MIRACLE trial as a recursive two-stage adaptive trial, which is a relatively new method for group sequential trials [4] [5] [6] [7] . The approach is based on the conditional error principle, which allows for flexible and continuous adjustment of the trial parameters using data observed during prior stages without inflation of the type I error [8] . Another advantage of this method is the flexibility in setting the timing and the number of needed interim analyses. Such flexibility is necessary in a situation where recruitment rate is unpredictable and a sudden flux in recruitment of patients could happen at any time. Finally, the design takes advantage of the accumulated information throughout the trial from every single recruited patient as opposed to a traditional two-study approach (pilot followed by the main trial).